tbuckley/cabot-search huggingface dataset:
Histone acetyltransferases CBP/p300 in tumorigenesis and CBP/p300 inhibitors as promising novel anticancer agents
Authors: Qingjuan Chen, Binhui Yang, Xiaochen Liu, Xu D. Zhang, Lirong Zhang, Tao Liu
Journal: Theranostics (2022)

The histone acetyltransferases CBP and p300, often referred to as CBP/p300 due to their sequence homology and functional overlap and co-operation, are emerging as critical drivers of oncogenesis in the past several years.CBP/p300 induces histone H3 lysine 27 acetylation (H3K27ac) at target gene promoters, enhancers and super-enhancers, thereby activating gene transcription.While earlier studies indicate that CBP/p300 deletion/loss can promote tumorigenesis, CBP/p300 have more recently been shown to be over-expressed in cancer cells and drug-resistant cancer cells, activate oncogene transcription and induce cancer cell proliferation, survival, tumorigenesis, metastasis, immune evasion and drug-resistance.Small molecule CBP/p300 histone acetyltransferase inhibitors, bromodomain inhibitors, CBP/p300 and BET bromodomain dual inhibitors and p300 protein degraders have recently been discovered.The CBP/p300 inhibitors and degraders reduce H3K27ac, down-regulate oncogene transcription, induce cancer cell growth inhibition and cell death, activate immune response, overcome drug resistance and suppress tumor progression in vivo.In addition, CBP/p300 inhibitors enhance the anticancer efficacy of chemotherapy, radiotherapy and epigenetic anticancer agents, including BET bromodomain inhibitors; and the combination therapies exert substantial anticancer effects in mouse models of human cancers including drug-resistant cancers.Currently, two CBP/p300 inhibitors are under clinical evaluation in patients with advanced and drug-resistant solid tumors or hematological malignancies.In summary, CBP/p300 have recently been identified as critical tumorigenic drivers, and CBP/p300 inhibitors and protein degraders are emerging as promising novel anticancer agents for clinical translation.
A multimodal imaging workflow for monitoring CAR T cell therapy against solid tumor from whole-body to single-cell level
Authors: Rita Pfeifer, Janina Henze, Katharina Wittich, Andre Gosselink, Ali Kinkhabwala, Felix Gremse, Cathrin Bleilevens, Kevin Bigott, Melanie Jungblut, Olaf Hardt, Frauke Alves, Wa'el Al Rawashdeh
Journal: Theranostics (2022)

CAR T cell research in solid tumors often lacks spatiotemporal information and therefore, there is a need for a molecular tomography to facilitate high-throughput preclinical monitoring of CAR T cells.Furthermore, a gap exists between macro-and microlevel imaging data to better assess intratumor infiltration of therapeutic cells.We addressed this challenge by combining 3D µComputer tomography bioluminescence tomography (µCT/BLT), light-sheet fluorescence microscopy (LSFM) and cyclic immunofluorescence (IF) staining.Methods: NSG mice with subcutaneous AsPC1 xenograft tumors were treated with EGFR CAR T cell (± IL-2) or control BDCA-2 CAR T cell (± IL-2) (n = 7 each).Therapeutic T cells were genetically modified to co-express the CAR of interest and the luciferase CBR2opt.IL-2 was administered s.c.under the xenograft tumor on days 1, 3, 5 and 7 post-therapy-initiation at a dose of 25,000 IU/mouse.CAR T cell distribution was measured in 2D BLI and 3D µCT/BLT every 3-4 days.On day 6, 4 tumors were excised for cyclic IF where tumor sections were stained with a panel of 25 antibodies.On day 6 and 13, 8 tumors were excised from rhodamine lectin-preinjected mice, permeabilized, stained for CD3 and imaged by LSFM.Results: 3D µCT/BLT revealed that CAR T cells pharmacokinetics is affected by antigen recognition, where CAR T cell tumor accumulation based on target-dependent infiltration was significantly increased in comparison to target-independent infiltration, and spleen accumulation was delayed.LSFM supported these findings and revealed higher T cell accumulation in target-positive groups at day 6, which also infiltrated the tumor deeper.Interestingly, LSFM showed that most CAR T cells accumulate at the tumor periphery and around vessels.Surprisingly, LSFM and cyclic IF revealed that local IL-2 application resulted in early-phase increased proliferation, but long-term overstimulation of CAR T cells, which halted the early added therapeutic effect.Conclusion: Overall, we demonstrated that 3D µCT/BLT is a valuable non-isotope-based technology for whole-body cell therapy monitoring and investigating CAR T cell pharmacokinetics.We also presented combining LSFM and MICS for ex vivo 3D-and 2D-microscopy tissue analysis to assess intratumoral therapeutic cell distribution and status.
Promising alternatives of CD47 monoclonal antibody: an injectable degradable hydrogel loaded with PQ912 for postoperative immunotherapy effectively blocks CD47-SIRPα signal
Authors: Chang Li, Yubo Liu, Dan Li, Qiu Wang, Shuang Zhou, Haotian Zhang, Yongjun Wang, Zhonggui He, Hongzhuo Liu, Jin Sun
Journal: Theranostics (2022)

Rationale: Many cancers have evolved different mechanisms to evade immune surveillance. Macrophages, the innate defense of the immune system, are limited in their phagocytosis by CD47 anti-phagocytic signaling expressed on the surface of tumor cells. Although the CD47 monoclonal antibody (aCD47) strategy has been extensively studied in clinical trials, the depletion of aCD47 by red blood cells (RBCs) and the resulting hematotoxicity have impeded their application in tumor treatment. Methods: Here, we reported an injectable hydrogel scaffold that allowed for local delivery of small-molecule inhibitor PQ912. The biodegradable hydrogel scaffold (PQ/PB-Gel) was formed by rapid cross-linking of tetra-armed PEG succinimidyl succinate (Tetra-PEG-SS) solution and alkalescent bovine serum albumin (BSA) solution through ammonolysis reaction. Results: PQ/PB-Gel had excellent effect on inhibiting local recurrence of two kinds of tumors. The hydrogel system inhibited the generation of "don't eat me" signals during the treatment cycle by inhibiting the expression of newly generated neoplastic CD47. Thus, it avoided adverse reactions such as erythrocytopenia after the use of aCD47 in terms of safety. After the "don't eat me" signal was blocked the clearance and recognition of cancer cells by macrophages and antigen-presenting cells were enhanced, sequentially systemic immune response was activated and further memory T lymphocyte (T cell) formation was induced. Conclusions: PQ/PB-Gel had a simple preparation and administration method, low production cost, excellent efficacy and low toxicity, so it had good practicability. This might provide a safe alternative strategy for aCD47 for inhibit local tumor recurrence and distal metastasis in postoperative immunotherapy.
Antibody-based drug delivery systems for cancer therapy: Mechanisms, challenges, and prospects
Authors: Zhoujiang Chen, Ranjith Kumar Kankala, Zhiyong Yang, Wei Li, Songzhi Xie, Hanmei Li, Ai-Zheng Chen, Liang Zou
Journal: Theranostics (2022)

In recent years, antibody-based cancer therapy has emerged as one of the efficient therapeutic strategies, such as immune checkpoint inhibitors (ICIs), angiogenesis inhibitors, antibody-drug conjugates (ADCs), multi-specific antibodies, and chimeric antigen receptor T (CAR-T) cells, among others.To date, various drug delivery platforms have been developed to improve the bioavailability, delivery convenience, and reduced toxicity towards increased therapeutic efficacy of antibodies.Herein, we emphasize the clinical manifestations of various antibody-based tumor therapies, highlighting their mechanisms and applications for cancer therapy.Further, based on the problems to be solved in the current clinical application of antibodies, and combined with the advanced drug delivery technologies, we discuss the roles of antibody-based drug delivery systems (DDSs) in cancer therapy, such as enhanced patient compliance and regulating the tumor microenvironment for combined therapy.By expounding the importance of DDSs and discussing the challenges and prospects of their implementation, we suggest that pharmaceutical enterprises and scientists develop appropriate antibody-based delivery platforms.
Dual-sensitive antibacterial peptide nanoparticles prevent dental caries
Authors: Peng Zhang, Saizhi Wu, Jinting Li, Xiaoshuang Bu, Xiaoping Dong, Ninglin Chen, Fengjiao Li, Jingyu Zhu, Longkang Sang, Youlin Zeng, Songping Liang, Zhilin Yu, Zhonghua Liu
Journal: Theranostics (2022)

Background: Dental caries is the most prevalent bacterial biofilm-induced disease.Current clinical prevention and treatment agents often suffer from adverse effects on oral microbiota diversity and normal tissues, predominately arising from the poor biofilm-targeting property of the agents.Methods: To address this concern, we herein report dual-sensitive antibacterial peptide nanoparticles pHly-1 NPs upon acid and lipid-binding for treatment of dental caries.Amino acid substitutions were performed to design the peptide pHly-1.The potential, morphology and secondary structure of pHly-1 were characterized to elucidate the mechanisms of its pH and lipid sensitivity.Bacterial membrane integrity assay and RNA-seq were applied to uncover the antimicrobial mechanism of peptides under acidic condition.The in vitro and ex vivo antibiofilm assays were used to determine the antibiofilm performance of pHly-1 NPs.We also carried out the in vivo anti-caries treatment by pHly-1 NPs on dental caries animal model.Oral microbiome and histopathological analyses were performed to assess the in vivo safety of pHly-1 NPs.Results: The pHly-1 peptide underwent the coil-helix conformational transition upon binding to bacterial membranes in the acidic cariogenic biofilm microenvironment, thereby killing cariogenic bacteria.Under normal physiological conditions, pHly-1 adopted a β-sheet conformation and formed nanofibers, resulting in negligible cytotoxicity towards oral microbes.However, in acidic solution, pHly-1 NPs displayed reliable antibacterial activity against Streptococcus mutans, including standard and clinically isolated strains, mainly via cell membrane disruption, and also suppressed in vitro and human-derived ex vivo biofilm development.Compared to the clinical agent chlorhexidine, in vivo topical treatment with pHly-1 NPs showed an advanced effect on inhibiting rat dental caries development without adverse effects on oral microbiota diversity and normal oral or gastric tissues.Conclusion: Our results demonstrated the high efficacy of dual-sensitive antimicrobial peptides for the selective damage of bacterial biofilms, providing an efficient strategy for preventing and treating dental caries.
PTPROt aggravates inflammation by enhancing NF-κB activation in liver macrophages during nonalcoholic steatohepatitis: Erratum
Authors: Kangpeng Jin, Yang Liu, Yuze Shi, Haitian Zhang, YuanYuan Sun, Guangyan Zhangyuan, Fei Wang, Weiwei Yu, Jincheng Wang, Xuewen Tao, Xin Chen, Wenjie Zhang, Beicheng Sun
Journal: Theranostics (2022)

[This corrects the article DOI: 10.7150/thno.42658.].
Molecular Imaging-Derived Biomarker of Cardiac Nerve Integrity — Introducing High NET Affinity PET Probe <sup>18</sup>F-AF78
Authors: Xinyu Chen, Rudolf A. Werner, Kazuhiro Koshino, Naoko Nose, Saskia Mühlig, Steven P Rowe, Martin G. Pomper, Constantin Lapa, Michael Decker, Takahiro Higuchi
Journal: Theranostics (2022)

Background: Radiolabeled agents that are substrates for the norepinephrine transporter (NET) can be used to quantify cardiac sympathetic nervous conditions and have been demonstrated to identify high-risk congestive heart failure (HF) patients prone to arrhythmic events.We aimed to fully characterize the kinetic profile of the novel 18 F-labeled NET probe AF78 for PET imaging of the cardiac sympathetic nervous system (SNS) among various species.Methods: 18 F-AF78 was compared to norepinephrine (NE) and established SNS radiotracers by employing in vitro cell assays, followed by an in vivo PET imaging approach with healthy rats, rabbits and nonhuman primates (NHPs).Additionally, chase protocols were performed in NHPs with NET inhibitor desipramine (DMI) and the NE releasing stimulator tyramine (TYR) to investigate retention kinetics in cardiac SNS.Results: Relative to other SNS radiotracers, 18 F-AF78 showed higher transport affinity via NET in a cell-based competitive uptake assay (IC50 0.42 ± 0.14 µM), almost identical to that of NE (IC50, 0.50 ± 0.16 µM, n.s.).In rabbits and NHPs, initial cardiac uptake was significantly reduced by NET inhibition.Furthermore, cardiac tracer retention was not affected by a DMI chase protocol but was markedly reduced by intermittent TYR chase, thereby suggesting that 18 F-AF78 is stored and can be released via the synaptic vesicular turnover process.Computational modeling hypothesized the formation of a T-shaped π-π stacking at the binding site, suggesting a rationale for the high affinity of 18 F-AF78.Conclusion: 18 F-AF78 demonstrated high in vitro NET affinity and advantageous in vivo radiotracer kinetics across various species, indicating that 18 F-AF78 is an SNS imaging agent with strong potential to guide specific interventions in cardiovascular medicine.
Extracellular vesicles as bioactive nanotherapeutics: An emerging paradigm for regenerative medicine
Authors: Min Li, Fang Fang, Meng Sun, Yinfeng Zhang, Min Hu, Jinfeng Zhang
Journal: Theranostics (2022)

In recent decades, extracellular vesicles (EVs), as bioactive cell-secreted nanoparticles which are involved in various physiological and pathological processes including cell proliferation, immune regulation, angiogenesis and tissue repair, have emerged as one of the most attractive nanotherapeutics for regenerative medicine. Herein we provide a systematic review of the latest progress of EVs for regenerative applications. Firstly, we will briefly introduce the biogenesis, function and isolation technology of EVs. Then, the underlying therapeutic mechanisms of the native unmodified EVs and engineering strategies of the modified EVs as regenerative entities will be discussed. Subsequently, the main focus will be placed on the tissue repair and regeneration applications of EVs on various organs including brain, heart, bone and cartilage, liver and kidney, as well as skin. More importantly, current clinical trials of EVs for regenerative medicine will also be briefly highlighted. Finally, the future challenges and insightful perspectives of the currently developed EV-based nanotherapeutics in biomedicine will be discussed. In short, the bioactive EV-based nanotherapeutics have opened new horizons for biologists, chemists, nanoscientists, pharmacists, as well as clinicians, making possible powerful tools and therapies for regenerative medicine.
Polymer chimera of stapled oncolytic peptide coupled with anti-PD-L1 peptide boosts immunotherapy of colorectal cancer
Authors: Lu Lu, He Zhang, Yudong Zhou, Jiayi Lin, Weidong Gao, Ting Yang, Jinmei Jin, Lijun Zhang, Dale G. Nagle, Weidong Zhang, Ye Wu, Hongzhuan Chen, Xin Luan
Journal: Theranostics (2022)

Rationale: Scarce tumor mutation burden and neoantigens create tremendous obstacles for an effective immunotherapy of colorectal cancer (CRC). Oncolytic peptides rise as a promising therapeutic approach that boosts tumor-specific immune responses by inducing antigenic substances. However, the clinical application of oncolytic peptides has been hindered because of structural instability, proteolytic degradation, and undesired toxicity when administered systemically. Methods: Based on wasp venom peptide, an optimized stapled oncolytic peptide MP9 was developed with rigid α-helix, protease-resistance, and CRC cell cytotoxicity. By incorporating four functional motifs that include D-peptidomimetic inhibitor of PD-L1, matrix metalloproteinase-2 (MMP-2) cleavable spacer, and MP9 with 4-arm PEG, a novel peptide-polymer conjugate (PEG-MP9-aPDL1) was obtained and identified as the most promising systemic delivery vehicle with PD-L1 targeting specificity and favorable pharmacokinetic properties. Results: We demonstrated that PEG-MP9-aPDL1-driven oncolysis induces a panel of immunogenic cell death (ICD)-relevant damage-associated molecular patterns (DAMPs) both in vitro and in vivo, which are key elements for immunotherapy with PD-L1 inhibitor. Further, PEG-MP9-aPDL1 exhibited prominent immunotherapeutic efficacy in a CRC mouse model characterized by tumor infiltration of CD8+ T cells and induction of cytotoxic lymphocytes (CTLs) in the spleens. Conclusion: Our findings suggest that PEG-MP9-aPDL1 is an all-in-one platform for oncolytic immunotherapy and immune checkpoint blockade (ICB).
The mechanistic pathways of oxidative stress in aortic stenosis and clinical implications
Authors: Kailun Phua, Nicholas WS Chew, William KF Kong, Ru-San Tan, Lei Ye, Kian-Keong Poh
Journal: Theranostics (2022)

Despite the elucidation of the pathways behind the development of aortic stenosis (AS), there remains no effective medical treatment to slow or reverse its progress.Instead, the gold standard of care in severe or symptomatic AS is replacement of the aortic valve.Oxidative stress is implicated, both directly as well as indirectly, in lipid infiltration, inflammation and fibro-calcification, all of which are key processes underlying the pathophysiology of degenerative AS.This culminates in the breakdown of the extracellular matrix, differentiation of the valvular interstitial cells into an osteogenic phenotype, and finally, calcium deposition as well as thickening of the aortic valve.Oxidative stress is thus a promising and potential therapeutic target for the treatment of AS.Several studies focusing on the mitigation of oxidative stress in the context of AS have shown some success in animal and in vitro models, however similar benefits have yet to be seen in clinical trials.Statin therapy, once thought to be the key to the treatment of AS, has yielded disappointing results, however newer lipid lowering therapies may hold some promise.Other potential therapies, such as manipulation of microRNAs, blockade of the renin-angiotensin-aldosterone system and the use of dipeptidylpeptidase-4 inhibitors will also be reviewed.
3D culturing of human pluripotent stem cells-derived endothelial cells for vascular regeneration
Authors: Edit Gara, Eleonora Zucchelli, Annamária Nemes, Zoltán Jakus, Kitti Ajtay, Éva Kemecsei, Gábor Kiszler, Nikolett Hegedűs, Krisztián Szigeti, Iván Földes, Kristóf Árvai, János Kósa, Kraszimir Kolev, Erzsébet Komorowicz, Parasuraman Padmanabhan, Pál Maurovich-Horvat, Edit Dósa, György Várady, Miklós Pólos, István Hartyánszky, Sian E. Harding, Béla Merkely, Domokos Máthé, Gábor Szabó, Tamás Radovits, Gábor Földes
Journal: Theranostics (2022)

Human induced pluripotent stem cell-derived endothelial cells can be candidates for engineering therapeutic vascular grafts.
Aptamers used for molecular imaging and theranostics - recent developments
Authors: Lennart Bohrmann, Tobias Burghardt, Charles Haynes, Katayoun Saatchi, Urs O. Häfeli
Journal: Theranostics (2022)

Aptamers are single stranded oligonucleotides that fold into three dimensional structures and are able to recognize a variety of molecular targets.Due to the similarity to antibodies with regards to specificity and affinity and their chemical versatility, aptamers are increasingly used to create targeted probes for in vivo molecular imaging and therapy.Hence, aptamer-based probes have been utilized in practically all major imaging modalities such as nuclear imaging, magnetic resonance imaging, x-ray computed tomography, echography and fluorescence imaging, as well as newer modalities such as surface enhanced Raman spectroscopy.Aside from targeting, aptamers have been used for the creation of sensors that allow the localized detection of cellular markers such as ATP in vivo.This review focuses on in vivo studies of aptamer-based probes for imaging and theranostics since the comprehensive overview by Bouvier-Müller and Ducongé in 2018.
5-HT2B-mediated serotonin activation in enterocytes suppresses colitis-associated cancer initiation and promotes cancer progression
Authors: Liyuan Mao, Fang Xin, Jie Ren, Shuai Xu, Haixia Huang, Xu Zha, Xinxin Wen, Guoqing Gu, Guang Yang, Yuan Cheng, Chen Zhang, Wei Wang, Xicheng Liu
Journal: Theranostics (2022)

Rationale: Serotonin (5-hydroxytryptamine, 5-HT) is generally considered to be involved in colitis-associated cancer (CAC), but previous research has yielded inconsistent results regarding the effect of 5-HT on CAC.5-HT2B is one of the receptors of 5-HT, and the receptor is expressed in intestinal epithelial cells (IECs).However, the functions of 5-HT2B in CAC remain unclear.Our work demonstrates the variable functions of 5-HT/5-HT2B signaling in the initiation and progression of CAC in mice.Methods: We constructed two types of mutant mice homozygous knockout of Htr2b, the gene encoding 5-HT2B, in IECs (Htr2b ΔIEC and Htr2b ΔIEC-ER ) to study the role of 5-HT2B in AOM/DSS-induced CAC model.Inflammation was measured using the body weight, colon length, and colitis severity score, and by histologic analysis of colon tissues.Tumor severity was assessed by tumor quantity, load, and histologic analysis of colon tumor tissues.Results: In Htr2b ΔIEC mice, AOM/DSS induced an enhancement of colitis and tumor severity.This process was due to the inhibition of TGF-β/SMAD signaling pathway and activation of IL-6/STAT3 signaling pathway.IL-6 antibody treatment reversed the stimulating effect of Htr2b deletion on tumorigenesis.However, tumor severity decreased in Htr2b ΔIEC-ER mice injected with tamoxifen on day 48 of AOM/DSS treatment.Knockout Akt1 eliminated the function of 5-HT in promoting tumor cells.Conclusion: Our work elucidates 5-HT/5-HT2B/TGF-β signaling as a critical tumor suppressing axis during CAC initiation but as a promoter of cancer progression in the late-stage of CAC.Our findings provide a new understanding of the role of 5-HT in the initiation and progression of CAC, offering a new perspective on the long-standing debate on whether the 5-HT signal promotes or inhibits tumors.
N<sup>6</sup>-methyladenosine-mediated LDHA induction potentiates chemoresistance of colorectal cancer cells through metabolic reprogramming
Authors: Kun Zhang, Tao Zhang, Yuhan Yang, Wenling Tu, Hongbin Huang, Yujun Wang, Yuzhuo Chen, Kejian Pan, Zhuojia Chen
Journal: Theranostics (2022)

Background: Chemoresistance to 5-fluorouracil (5-FU) is a major barrier to influence the treatment efficiency of colorectal cancer (CRC) patients, while the precise molecular mechanisms underlying 5-FU resistance remain to be fully elucidated.Methods: The metabolic profiles including ATP generation, glucose consumption, lactate generation, and oxygen consumption rate (OCR) in 5-FU resistant CRC cells were compared with those in their parental cells.Subsequently, a series of in vitro and in vivo experiments were carried out to investigate the mechanisms responsible for metabolic reprogramming of 5-FU resistant CRC cells.Results: We found that 5-FU resistant CRC cells showed increased levels of ATP generation, glucose consumption, lactate generation, and OCR as compared with those in their parental cells.Further, increased levels of mRNA N 6 -methyladenosine (m 6 A) and methyltransferase-like 3 (METTL3) were observed in 5-FU resistant CRC cells.Inhibition or knockdown of METTL3 can suppress glycolysis and restore chemosensitivity of 5-FU resistant CRC cells.Mechanistically, METTL3 enhances the expression of LDHA, which catalyzes the conversion of pyruvate to lactate, to trigger glycolysis and 5-FU resistance.METTL3 can increase the transcription of LDHA via stabilizing mRNA of hypoxia-inducible factor (HIF-1α), further, METTL3 also triggers the translation of LDHA mRNA via methylation of its CDS region and recruitment of YTH domain-containing family protein 1 (YTHDF1).Targeted inhibition of METTL3/LDHA axis can significantly increase the in vitro and in vivo 5-FU sensitivity of CRC cells. Conclusion:Our study indicates that METTL3/LDHA axis-induced glucose metabolism is a potential therapy target to overcome 5-FU resistance in CRC cells.